The administration of active agents in medical, veterinary or agricultural applications requires formulations that afford suitable availability of the active agent with minimal doses and an acceptable level of adverse effects.
Classically, physicians have administered toxic medicaments to patients in relatively high dosages, with spaced-apart dosage regimens. The percent efficiency of such administration is relatively low. Furthermore, there is often a limit on the cumulative quantity of a drug that can be administered to the patient. There has thus been a trend, over the last few decades, to attempt to provide slow release compositions of the medicaments or drugs.
The administration of active agents in agriculture suffers from the same trends as noted above with regard to medicaments. Typically a pesticide or other active agent is administered to the agricultural environment in large quantities but with little effect to the target organism and detrimental effects to many other non-targeted organisms. There is thus a need to provide agricultural agents in effective slow release, non-toxic forms with low risk:benefit ratios.
Different types of slow-release formulations of drugs and agricultural agents have been investigated, including, but not limited to, liposomes, inert carriers, and colloidal carriers.
It is known in the art that a variety of hydrocolloids have been studied for their potential use as carriers for the controlled release of compounds, including drugs and agro-chemical compounds, such as those used for pest control. Several studies have focused on alginate-based carriers, revealing some difficulties. For one, the loading efficacy of the active ingredient (drug, agro-chemical compound) is too low due to its leakage into the cross-linking solution (1, 2).
The evaluation of drug-carrier efficacy is not simple, because release profiles vary with pH (1, 3). Active compound solubility can be influenced by the pH of the dissolution medium (4), as can the stability of other components of the formulation. For example, Eudragit, which is soluble at a pH above 6, is often used as a coating material in extended drug-release formulations (5). Therefore, carriers should be examined in a continuous simulated ambient model which, for orally administered drugs, is the gastrointestinal model and, for agro-chemical uses, is soil. Combinations of alginate with other hydrocolloids have also been reported (6, 7). Less information can be found on carriers based on guar gum (8), and even fewer studies have focused on gellan, agar and agarose or other hydrocolloid gelling agents which have the potential for carrier manufacturing (9, 10).
Formulations based on hydrocolloids may have some advantages over other sustained-release formulations. For instance, different structures can be obtained upon dehydration of the hydrocolloid formulations. These structures can be modified by the drying conditions and formulation composition. Structural characteristics, such as porosity, may affect the penetration rate of liquid into the formulations and thus modify the release pattern of the drug.
Moreover, the stability and physical properties (dimensions, strength, etc.) of various hydrocolloids are affected by factors such as swelling in water, pH value, and enzymes, and therefore vary in different parts of the gastrointestinal tract. Changes in the physical properties of the formulations may also lead to different drug-release patterns in different parts of the gastrointestinal tract.
Thus, hydrocolloids can be used as carriers for the controlled release of drugs. In addition, hydrocolloid-formulation preparation procedures are generally quite simple and the cost of such materials is low (11).
U.S. Pat. No. 4,818,530 to Marois, et al. discloses pellets containing living biocontrol fungi in an alginate mixture. Various organic and inorganic fillers, preferably pyrophillite, are disclosed among a long list of additional optional adjuvants that may be incorporated into the formulations. The fillers are an optional ingredient, and not disclosed as imparting any requisite structural or mechanical properties to the pellets.
U.S. Pat. No. 6,297,033, to one of the inventors of the present invention and co-workers, discloses permeable polymeric beads which contain a combination of fermentative and denitrifying bacteria and a carbon source, for use in a system for nitrate removal from aquariums. The carbon source used is preferably potato starch, and is not disclosed as imparting any structural or mechanical properties to the beads.
U.S. Pat. No. 6,589,328 to one of the inventors of the present invention, discloses hydrocolloid sponges produced by preparing a gel of a hydrocolloid, and either sealing it in a closed vessel with a liquid of similar composition, pressurizing the vessel and abruptly releasing the pressure, followed by freeze drying, or by incorporating in such a gel a suitable microorganism, such as a yeast, and inducing fermentation in the presence of a suitable nutrient medium, so that the carbon dioxide formed results in expansion and foam formation, which is processed to the final product.
Zohar-Perez, et al. (20) disclose irregular textural features of dried alginate-filler beads, having up to 0.5% (w/w) of bentonite or kaolin as fillers. These beads are further reported to provide extra protection for microorganisms against UV radiation (24).
US Patent Application Publication Number 2003/0224022 to one of the inventors of the present invention, discloses hydrocolloid cellular solid matrices that are useful as carriers for a variety of substances.
U.S. Pat. No. 7,022,313, to O'Connor, et al., discloses new compositions formed from the combination of an active substance with a hydrogel carrier moiety. The compositions are suitable for use in high-velocity transdermal particle injection techniques. Methods of providing the new compositions are also provided. In addition, methods for administering pharmacologically active agents to a subject are provided. These methods are useful for delivering drugs, biopharmaceuticals, vaccines and diagnostics agents.
U.S. Pat. No. 7,189,275, to Pildysh, describes a permeable composition, a controlled release product, and methods for producing the permeable composition and controlled release product. The permeable composition includes a matrix material, a particulate filler material, and interfacial passageways between the matrix material and the particles of filler material. The matrix material may include a substrate material and a carrier material. The controlled release product is formed by coating a substrate material with at least one layer of the permeable composition. The methods include the steps of applying a degradable surface treatment material to the particles of filler material and then dispersing the surface treated filler material throughout the matrix material so that degradable interfaces are provided between the matrix material and the particles of filler material.
After the priority date of the present application, the inventors published a report on hydrocolloid carriers with filler inclusion for use in slow release of the pharmaceutical agent diltiazem hydrochloride (25). Diltiazem hydrochloride is a calcium antagonist used to moderate systemic hypertension. Anti-arrhythmic effects of the drug control the ventricular response to atrial fibrillation and flutter. This compound is also used for the treatment of stable and unstable angina pectoris. Although most of the administered drug dose is absorbed (90%), its bioavailability only reaches 30 to 65% because of a high first-pass effect, mainly in the liver and the gastro-intestinal tract (12). Diltiazem hydrochloride has a short plasma half-life of 3 to 4 h (13, 14) and is taken 3 to 4 times a day. Therefore, controlled/sustained-release formulations for diltiazem hydrochloride are needed.
There thus remains an unmet need for safer, more efficient and more effective ways of delivering medicaments to patients and agricultural agents to a specific organism or crop in the environment.